COX-2-derived prostaglandins from the macula densa are important modulators of renin expression and renal hemodynamics, while COX-2-derived prostaglandins in the medulla mediate natriuresis and diuresis. There is also increasing evidence that COX-2 metabolites are mediators of renal pathophysiology associated with chronic renal disease. Although COX-2 inhibitors ameliorate renal injury in experimental animal models, these inhibitors can promote thrombotic vascular injury and raise blood pressure, which limits their clinical use in patients with progressive renal disease. Therefore, there remains a need to identify other mechanisms to selectively inhibit the increased renal cortical COX-2 expression and activity seen in renal disease, preferably while sparing medullary COX-2 expression and activity. The dopaminergic system is a crucial intrarenal regulatory system that is responsible for >50% of the net diuresis and natriuresis occurring in response to volume expansion or dietary salt excess. Increasing evidence also indicates that there is abnormal intrarenal dopamine expression and activity in essential hypertension and in diabetes mellitus, but the pathophysiologic consequences have yet to be explored in detail. Our preliminary studies examining the interaction of the intrarenal dopaminergic and COX-2 systems have determined potentially important roles for this axis in renal physiology and pathophysiology. We propose that modulation of renal COX-2 expression and/or activity plays a crucial role in the physiologic functions of intrarenal dopamine and that altered intrarenal dopamine production and activity in both hypertension and diabetes play a significant role in the associated renal pathophysiology, due in part to alterations in COX-2 expression and function. The proposed studies will utilize unique mouse models with selectively altered intrarenal dopamine levels. We propose three specific aims: Aim 1 will examine the interaction of intrarenal dopaminergic and COX-2 systems in regulation of renal physiology: Aim 2 will determine the role of the interactions of the intrarenal dopaminergic and COX-2 systems in development and maintenance of hypertension;and Aim 3 will examine potential roles of these interactions in development of diabetic nephropathy. We predict that these studies will provide important information about whether modulating the intrarenal dopaminergic system could be a potential therapeutic strategy to alter intrarenal COX-2 expression and activity in progressive renal injury. PUBLIC HEALTH RELEVANCE Hormonal systems intrinsic to the kidney are essential for regulation of blood pressure and salt and water excretion under normal conditions, and dysregulation of these processes in hypertension and diabetes may contribute to progressive kidney injury. The physiologic and pathophysiologic interactions of these systems, the intrarenal dopaminergic system, the renin angiotensin system and the cyclooxygenase-2 system, are the focus of the proposed studies.